EP0756480B1 - Sustained-release matrix pellets and method for preparing them - Google Patents

Abstract

Slow-release matrix pellets with a spherical or lenticular shape and uniform maximum diameters in the range from 0.5 to 4 mm, composed ofa) 0.1-87% by weight of at least one biologically active compound,b) 5-50% by weight of at least one water-insoluble polymer,c) 5-45% by weight of at least one lipophilic component as plasticizer for polymer b),d) 3-40% by weight of a natural or semisynthetic gel former,e) 0-50% by weight of one or more conventional formulation aids.

Description

The invention relates to a solid, preferably pharmaceutical, Retard form (pellets), in which the active ingredient in a mixture of a water-insoluble polymer, a lipid and a colloidal highly viscous water-soluble, gel-forming or at least water-swellable polymer is embedded. The production takes place in a one-step, continuous process Melt extrusion and shaping, preferably by hot cutting.

State of the art

Suitable matrix substances for melt extrusion and retardation are polymers and lipids that can be plasticized under pressure and temperature. Speiser et al. describe in Pharm. Acta Helv. 46 , 31 (1971) the use of gastric juice-soluble epoxy amine resins and intestinal juice-soluble copolymers of vinyl acetate / crotonic acid for injection-molded pharmaceutical forms (cf. what has been said about US 3,432,592). Hüttenrauch and Schmeiss investigated the release of model active ingredients from a polyethylene matrix produced by piston extrusion (Pharmazie 30 , 229, 536 (1975)).
Mank et al. describe in Pharmazie 44 , 773 (1989) and ibid. 45 , 592 (1990) the active ingredient release from insoluble thermoplastic matrices. These methods do not allow a freely adjustable retardation, and the active ingredient is not released completely, in particular from the polyethylene matrices. In addition, this method has the disadvantages of injection molding, such as a long dwell time at high temperature and high material losses through the sprue channels, the contents of which must not be reused. In addition, the molding costs are extremely high relative to the production speed.

NA El Gindy et al. describe in Acta Pharm. Technol. 33 , 208-211 (1987) the production of tablets by melting mixtures of active ingredients with water-soluble (polyethylene glycols and polyoxyethylene-polyoxypropylene block copolymers) and insoluble polymers and subsequent pressing. Due to the choice of polymer, these forms are more or less quick-releasing. The manufacturing process is discontinuous.

N. Follonier et al. report in Capsule News 1 (1991), 2 and in Abstract of the 6th International Conference on Pharmaceutical Technology, Paris, France, June 2-4, 1992, on manufacturing from sustained-release pellets by melt extrusion a single screw extruder. The solidified extrudate shredded one in a knife pelletizer. Water-insoluble was used as the matrix Polymers. In addition to the pellet size, various Additives to control the release of active substances were examined. The polymer base was primarily an ethylene-vinyl acetate copolymer. A release of the active ingredient from these forms after However, "zero-order kinetics" did not succeed.

No. 3,432,592 describes the injection molding of polymer melts containing active ingredients. The polymers used there should be at least partially soluble in the digestive juices. The soluble polymer is predominantly described as a complex condensation product of an aminodiol and an epoxide, which is not common in the pharmaceutical sector. Retardation is achieved through the use of thermoplastics that are difficult to dissolve in the digestive juices. The polymer combinations given there are not suitable for the retardation of well water-soluble active substances from pellets due to the unfavorable surface / volume ratio. In general, it is difficult to control the retardation according to this procedure, in the case of severe retardation a part of the active ingredient remains undissolved in the pellets (release of the active ingredient afterwards) t -Law; s. T. Higuchi, J. Pharm. Sci. 52 , 1145-1149 (1963)). A release according to "zero order kinetics" does not succeed (see Table I).

The extrusion of active ingredient-containing polymer melts, preferably of vinyl pyrrolidone copolymers, is from EP-A 240 904 and EP-A 240 906 known. The setting of a specific drug release profile about polymer blends is not listed there. In addition, it has been shown that the so produced In many cases, products are not very stable in storage, the retard effect decreases with time.

EP-B 204 596 describes the production of pellets by embedding of an active ingredient in a matrix of the following components: At least one non-hydrophilic polymer and either one Mixture of at least two lipid substances, one of which is the or the polymer dissolving or gelling properties and the other lubricant properties, or a lipid substance, which combines the two properties mentioned, and optionally one or more additives selected from Extenders and antistatic agents. Serious disadvantages: With higher amounts (from approx. 20%) of "non-hydrophilic polymer" the release for a prolonged-release product takes place too quickly, with less Quantities the release changes greatly during storage, and it is incomplete.

In EP-A 544 144 there are solid pharmaceutical slow release forms described by melt extrusion of mixtures of a Pharmaceutical active ingredient obtained with a polymer mixture be, the polymer mixture at least one water-insoluble Pol (meth) acrylate and a water-soluble hydroxyalkyl cellulose derivative or an N-vinylpyrrolidone polymer or mixtures thereof.

The invention was based, pellets, preferably for the task to produce pharmaceutical purposes from which the active ingredient with adjustable retard profile, so delayed as desired - but completely -, is released. This goal should be through matrix pellets can be realized, i.e. without being applied to the pellet core retarding film covers.

In addition to controlling the release of the active ingredient through the composition of the matrix (matrix retard pellets) should be a technique for developed simple inexpensive manufacture of these pellets become. This process should be continuous and one-step without previous mixing or pre-granulation of the components and without final spheronization or similar shaping / Rounding off the pellets after the manufacturing process.

solution

It has now been found that it is determined by melt extrusion active ingredient-containing polymer matrices and subsequent continuous Shaping succeeds in a simple way with extended release pellets high active substance contents, also of very well water-soluble active substances, produce, differing solely by the composition the polymer matrix without diffusion-controlling polymer coatings adjustable release profiles with wide ranges achieve high shelf life.

The basic principle of the polymer matrix according to the invention is one matrix plasticized by suitable lipophilic substances an insoluble in water and gastrointestinal fluids Polymers. In contrast to the prior art mentioned above a retard profile that can be freely adjusted over a wide range is now successful, if additionally in the matrix of insoluble polymer and lipophilic component a gelling agent, i.e. a highly viscous in water soluble (hydrocolloid) or at least swellable polymer is installed. With the matrices mentioned above in the prior art is the release of the active ingredient over the concentration controlled on insoluble polymer, with too little Amount of polymer there is a risk that the dosage form disintegrates if too much polymer is used however, the drug release will be incomplete, proportions of the active ingredient are completely included and are not available. The addition of gelling agent according to the invention results in a "Breaking" of the sustained-release matrix achieved by swelling of this polymer, the active substance can be released completely (cf. Tab. I).

The polymer matrix according to the invention for the matrix sustained release pellets is a new combination of inert, lipophilic and hydrophilic Matrix, can be processed thermoplastically.

a) mindestens eine biologisch wirksame Verbindung ("Wirkstoff"; vorzugsweise human- oder veterinär-med., aber auch Vitamine sowie systemische Insektizide, Fungizide und Herbizide) in einer Menge von 0,1 bis 87, vorzugsweise 1 bis 75, insbesondere 45 bis 75 Gew.-%,

b) mindestens ein in Wasser und gastrointestinalen Flüssigkeiten unlösliches natürliches, halbsynthetisches oder synthetisches Polymer in einer Menge von 5 bis 50, vorzugsweise 10 bis 40 Gew.-%,

c) 5 bis 45, vorzugsweise 10 bis 35 Gew.-% mindestens einer wasserunlöslichen liphophilen Komponente mit Weichmachereigenschaften bezüglich des Polymeren b) und Gleit- bzw. Schmiermitteleigenschaften,

d) 3 bis 40, vorzugsweise 5 bis 25 Gew.-% mindestens eines in Wasser oder gastrointestinalen Flüssigkeiten kolloidal löslichen, hochviskose Lösungen oder Gele bildenden oder mindestens quellbaren natrülichen oder halbsynthetischen hydrophilen Polymeren (hier kurz "Gelbildner" genannt), und

e) 0 bis 50, vorzugsweise 0 bis 40 Gew.-% eines oder mehrerer der üblichen Formulierungshilfsstoffe.

The subject of the invention is therefore a solid pharmaceutical slow-release form (matrix pellets), produced in a one-step process by melt extrusion in an extruder, preferably a twin-screw extruder or a single-screw extruder with a mixing compartment, at 50 to 200 ° C. and continuous shaping (preferably Hot cutting) of a mixture of the following composition:

a) at least one biologically active compound ("active ingredient"; preferably human or veterinary, but also vitamins and systemic insecticides, fungicides and herbicides) in an amount of 0.1 to 87, preferably 1 to 75, in particular 45 to 75% by weight,

b) at least one natural, semisynthetic or synthetic polymer insoluble in water and gastrointestinal liquids in an amount of 5 to 50, preferably 10 to 40% by weight,

c) 5 to 45, preferably 10 to 35% by weight of at least one water-insoluble lipophilic component with plasticizer properties with regard to the polymer b) and lubricant or lubricant properties,

d) 3 to 40, preferably 5 to 25% by weight of at least one colloidally soluble in water or gastrointestinal fluids, highly viscous solutions or gels or at least swellable natural or semisynthetic hydrophilic polymers (here called "gelling agents" for short), and

e) 0 to 50, preferably 0 to 40% by weight of one or more of the customary formulation auxiliaries.

The percentages relate to the total weight the pellets.

Solid pharmaceutical slow release forms are in the sense of the invention e.g. Granules, preferably pellets, with delayed release of active ingredient. The moldings obtained can also subsequently Powder is ground and used in this form (e.g. in Hard gelatin capsules). Subsequent covering of the moldings with taste-covering film coatings as they are state of the art (e.g. with polyacrylates, cellulose esters such as hydroxypropylmethyl cellulose phthalates and cellulose ethers such as ethyl cellulose, Hydroxypropylmethyl cellulose or hydroxypropyl cellulose) not excluded, but is generally not necessary.

Pressing the pellets into tablets is possible in many cases. This pressing is available, among other things. in cases where the Active substance dose is high and thus undesirably large dosage forms would result. By controlling the tableting conditions (especially baling pressure) may individual pellets disintegrate, so the drug release is not significantly different from analog pellets must be different, which (loose) were filled into capsules. The Compression to tablets leads to a reduction in volume Dosage form, which can be advantageous in individual cases. By encore osmotically active agents (e.g. inorganic salts) can pellets are also obtained which are considered to be osmotically active Source layer can be used (cf. WO 92/04011) to the Drug delivery e.g. from tablets (after pressing) or capsules to effect via an osmosis principle.

Pharmaceutical active substances a) are within the meaning of the invention all substances with a pharmaceutical effect and as low as possible To understand side effects, provided they are among the Do not decompose processing conditions. The amount of active ingredient per Dose unit and concentration can vary depending on the effectiveness and desired release rate within wide limits vary. The only condition is that they are used to achieve the the desired effect is sufficient. So the drug concentration in the range of 0.1 to 87, preferably 1 to 80, in particular 45 to 75 wt .-% lie. Active substances in the sense of the invention are, as mentioned, other biologically active Links. Preferred are betamethasone, thioctic acid, sotalol, Salbutamol, norfenefrin, silymarin, dihydroergotamine, buflomedil, Etofibrate, indomethacin, oxazepam, beta-acetyldigoxime, piroxicam, Haloperidol, ISMN, amitriptyline, diclofenac, nifedipine, Verapamil, pyritinol, nitrendipine, doxycycline, bromhexine, methylprednisolone, Clonidine, fenofibrate, allopurinol, pirenzepin, levothyroxine, Tamoxifen, metildigoxin, o- (beta-hydroxyethyl) rutoside, Propicillin, aciclovir mononitrate, paracetamol, naftidrofuryl, Pentoxyfylline, propafenone, acebutolol, L-thyroxine, tramadol, bromocriptine, Loperamide, ketotifen, fenoterol, Ca-Dobelisat, propranolol, Minocycline, nicergoline, ambroxol, metoprolol, beta-sitosterol, Enalapril hydrogen maleate, benzafibrate, ISDN, gallopamil, Xantinol nicotinate, digitoxin, flunitrazepan, bencyclan, dexapanthenol, Pindolol, lorazepam, diltiazem, piracetam, phenoxymethylpenicillin, Furosemide, bromazepam, flunarizine, erythromycin, Metoclopramide, acemetacin, ranitidine, biperiden, metamizole, Doxepin, dipotassium chlorazepate, tetrazepam, estramustine phosphate, Terbutaline, captopril, maprotilin, prazosin, atenolol, Glibenclamide, cefaclor, etilefrin, cimetidine, theophylline, hydromorphone, Ibuprofen, primidone, clobazam, oxaceprol, medroxyprogesterone, Flecainide, Mg-pyridoxal-5-phosphate glutaminate, hymechromone, Etofylline clofibrate, vincamine, cinnarizine, diazepam, Ketoprofen, flupentixol, molsidomine, glibornuride, dimetindene, Melperon, soquinolol, dihydrocodeine, clomethiazole, clemastine, Glisoxepid, kallidinogenase, oxyfedrine, baclofen, carboxymethylcysteine, Thioridacin, betahistin, L-tryptophan, myrtol, bromalaine, Prenylamine, salazosulfa pyridine, astemizole, sulpiride, Benzerazide, dibenzepine, acetylsalicylic acid, miconazole, nystatin, Ketoconazole, sodium picosulfate, colestyramine, gemfibrocil, rifampicin, Fluorocortolone, mexiletine, amoxicillin, terfenadrin, mucopolysaccharide poly sulfuric acid ester, Triazolam, mianserin, tiaprofenic acid, Amezinium Metilsulfat, Mefloquin, Probucol, Quinidine, Carbamepine, Mg-L-aspartate, penbutolol, piretanide, amitriptyline, Cyproterone, sodium valpropinate, mebeverin, bisacodyl, 5-amino-salicylic acid, Dihydralazine, magaldrate, phenprocoumon, amantadine, Naproxen, Carteolol, Famotidin, Methyldopa, Auranofin, Estriol, Nadolol, levomepromazine, doxorubicin, medofenoxate, azathioprine, Flutamide, norfloxacin, fendilin, prajmalium bitartrate, aescin.

Solid solutions of the following active ingredients are particularly preferred: Acetaminophen (= paracetamol), acetohexamide, acetyldigoxime, acetylsalicylic acid, Acromycin, anipamil, benzocaine, beta-carotene, Chloramphenicol, chlordiazepoxide, chlormadinoacetate, chlorothiazide, Cinnarizine, clonazepam, codeine, dexamethasone, diazepam, dicumarol, Digitoxin, digoxin, dihydroergotamine, drotaverine, flunitrazepam, Furosemide, gramicidin, griseofluvin, hexobarbital, hydrochlorothiazide, Hydrocortisone, hydroflumethazide, indimethazine, Ketoprofen, lonetil, medazepam, mefruside, methandrostenolone, methylprednisolone, Methylsulfadiazine (= sulfaperin), nalidixic acid, Nifedipine, nitrazepam, nitrofurantoin, nystatin, estradiol, Papaverine, phenacetin, phenobarbital, phenylbutazone, phenytoin, Prednisone, reserpine, spironolactone, streptomycin, sulfadimidine (= Sulfamethazine), sulfamethizole, sulfamethoxazole (= sulfameter), Sulfaperin, sulfathiazole, sulfisoxazole, testosterone, tolazamide, Tolbutamide, trimethoprim, tyrothricin.

The term "solid solutions" is familiar to the person skilled in the art, see Chiou and Riegelman, J. Pharm. Sci. 60 , 1281-1302 (1971). In solid solutions of active substances in polymers, the active substance is present in the matrix in a molecularly dispersed manner.

The natural, insoluble in water and gastrointestinal fluids, semi-synthetic or synthetic polymer b) can e.g. a cellulose ether such as ethyl cellulose or a cellulose ester such as Cellulose diacetate, cellulose triacetate, cellulose acetate propionate and cellulose acetate butyrate. Beyond that also insoluble polysaccharides such as chitin and chitin derivatives and Use microcrystalline cellulose. Examples of suitable synthetic Polymers are poly (meth) acrylic acid esters, homo- and Copolymers of vinyl acetate and the like Ethyl celluloses are preferred.

The water-insoluble lipophilic component c) with softening Properties relating to the polymer b) and lubricant properties can e.g. a fatty alcohol such as cetyl or Stearyl alcohol, a fatty acid such as stearic acid or a wax, for example ester wax based on montan wax. According to the invention, e.g. polyoxethylated Fatty alcohols, fatty acids and vegetable oils, hydrogenated vegetable oils, Mono-, di- and triglycerides as well as lecithins. Beyond that Polyglycerol fatty acid esters, saturated polyoxethylated glycerides, Polyethylene oxides, polypropylene oxides or their block copolymers, Phthalic acid esters, acetylated monoglycerides can be used. Mono-, di- or triglycerides or mixtures thereof are preferred and polyglycerol fatty acid esters. Lipophilic are preferred Components c) with an HLB (hydrophilic / lipophilic balance) value from 1 to 9, in particular 2 to 5.

As a gelling agent d), i.e. highly viscous colloidal solutions in water or gelling or at least swelling polymers in water, water-soluble cellulose derivatives are particularly suitable such as alkyl celluloses, hydroxyalkyl celluloses, hydroxyalkyl allyl celluloses, e.g. Methyl cellulose, hydroxymethyl cellulose, Hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, Hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose; also carboxyalkyl celluloses, carboxyalkyl alkyl celluloses, carboxyalkyl cellulose esters, e.g. Carboxymethyl cellulose and its alkali salts; they can also use other water-soluble polysaccharides such as alginic acids and their salts (alginates), carrageenans, Guar gum, xanthan gum, agar agar, gum arabic and related Gums, pectins, galactomannans, tragacanth, and also water-soluble Chitin derivatives such as chitosan. Water-soluble alkyl celluloses are preferred, Hydroxyalkyl celluloses or hydroxyalkyl alkyl celluloses, which as a 2% solution in water at 20 ° C has a viscosity over 1000 cps, preferably from 3500 to 120,000 cps. Hydroxypropylmethyl celluloses are also particularly preferred a degree of methylation from 1.36 to 1.81 and a degree of hydroxypropylation from 0.12 to 0.23, as well as hydroxypropyl celluloses.

Synergistic viscosity increases through mixtures of the polymer components, for example hydroxypropyl celluloses with anionic Polymers such as carboxymethyl celluloses or sodium alginate, are particularly advantageous.

"Water-soluble" means that there is at least one in 100 grams of water at 20 ° C 0.5, preferably at least 2 grams of the polymer colloidal to solve.

) As polymer component d) also come in water or intestinal Liquid insoluble but hydrophilic swellable polymers such as cross-linked polyvinylpyrrolidone or cross-linked starches, starch derivatives such as sodium starch glycolate, croscarmellose sodium, low substituted hydroxyl propyl cellulose and low substituted cross-linked sodium carboxymethyl cellulose in question.

Crucial for the suitability of a polymer as component d) is that it is hydrophilic on the one hand, but not too dissolves quickly in the digestive tract. On the one hand, it should Allow the active ingredient to diffuse out of the interior of the pellets, on the other hand, this should only be done slowly. Therefore it should form a gel or a highly viscous solution with water. The choice of this component and its quantity has crucial Influence on the retardation effect. It has surprisingly been shown that the above natural or semi-synthetic hydrophilic, gel-forming polymers - in contrast to fully synthetic Polymers such as PVP or vinyl pyrrolidone-vinyl acetate copolymers - high storage stability (constancy of the retard effect when storing) guarantee.

Component e) can be one or more of those for such Common auxiliary substances exist, such as fillers, lubricants, Mold release agents, plasticizers, blowing agents, stabilizers, Dyes, extenders, flow agents and their mixtures. Examples of fillers are inorganic fillers such as that Oxides of magnesium, aluminum, silicon, titanium etc. as well as microcrystals. Cellulose and cellulose powder, various strengths and their breakdown products (maltodextrins), lactose, mannitol, calcium diphosphate in a concentration of 0.02 to 50, preferably of 0.20 to 20% by weight, based on the total weight of the pellets.

Examples of lubricants are stearates of aluminum and Calcium as well as talc and silicone in a concentration of 0.1 to 5, preferably from 0.1 to 3 wt .-%, based on the total weight the pellets.

Examples of plasticizers include low molecular weight Poly (alkylene oxides), such as poly (ethylene glycols), poly (propylene glycols), Poly (ethylene-propylene glycols); with organic plasticizers low molecular weight such as glycerol, pentaerythritol, glycerol monoacetate, Diacetate or triacetate, propylene glycol, sorbitol, Sodium diethyl sulfone succinate added in concentrations of 0.5 to 15, preferably from 0.5 to 5 wt.%, Based on the total weight the pellets.

Examples of dyes are known azo dyes, organic and inorganic pigments, or colorants of natural origin. Inorganic pigments are preferred, in concentrations of 0.001 to 10, preferably from 0.5 to 3 wt .-%, based on the Total pellet weight.

In the context of the invention, auxiliary substances are also to be understood as meaning substances for producing a solid solution with the active pharmaceutical ingredient. These auxiliaries are, for example, sugars and sugar alcohols such as mannitol, sorbitol, xylitol, also urea, pentaerythritol and pentaerythritol tetraacetate, polymers such as polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as Polyoxyethylene-40-stearate as well as citric and succinic acid, bile acids, sterols and others as for example given by JL Ford, Pharm. Acta Helv. 61 , 69-88 (1986).

Additions of bases or acids to control the solubility of an active ingredient are also considered pharmaceutical auxiliaries (see, for example, K. Thoma et al., Pharm. Ind. 51 , 98-101 (1989)).

Mixing the active ingredient or ingredients with the polymer Binders and, if appropriate, other conventional pharmaceutical additives can be before or after melting the polymeric binder according to the usual procedures in the art. Prefers mixing in the extruder, preferably a twin-screw extruder or a single-screw extruder with a mixing compartment.

The polymeric binder mixture should be in the overall mixture of all Components in the range from 50 to 200, preferably 50 to 180, especially soften or melt 60 to 150 ° C, so that the Mass is extrudable.

The melts are solvent-free. This means that none Water and no organic solvent is added.

The shaping takes place by melt extrusion at 50 to 200, preferably 50 to 180, in particular 60 to 150 ° C and subsequent continuous deformation of the still plastic Strands, e.g. by shaping into tablets, for example according to EP-A 240 906 by passing the strand between two in opposite directions driven rollers with opposite one another Recesses in the roll shell, the execution of the tablet shape certainly. Cold cutting is also an option.

The so-called hot cut is preferred. The Strands immediately after exiting the nozzle assembly on Extruder by, for example, rotating knives or another suitable arrangement crushed, appropriately into pieces, the Length is approximately equal to the strand diameter. This chipped Melt particles cool in the air or gas flow to such an extent that the surface from contact with other particles or a vessel wall is already tack-free, on the other hand the particles but are still so plastic that they can be damaged by collisions, e.g. with the wall of a connected cyclone, a spherical Taking form. In this way, largely spherical or lenticular particles with diameters from 0.5 to 4, preferably 0.8 to 2 mm. The preferred smaller particles are primarily suitable for filling capsules.

The invention allows in a simple and environmentally friendly manner (without solvent) the production of slow release matrix pellets, which within wide limits with regard to their drug release are controllable. The delayed drug release succeeds without Application of a controlling film coating made of organic Solvents or aqueous dispersions would have to be applied and would require a drying step. The drug release takes place after erosion and diffusion control. The invention opens up the possibility of pH-independent drug release to achieve. The forms of the invention are for active ingredients with very different solution properties suitable. The retarding effect can be extraordinary even with small retard forms be strongly adjusted. The procedure allows the production of solid solutions of the active ingredients in the matrix polymer through melting technology without the use of organic solvents. Solid solutions are characterized by improved bioavailability out. The process is very economical because it is continuous, it is superior to traditional pelleting processes. The pellets according to the invention can have a high proportion of active ingredient exhibit. The spread of drug release is due to the good homogeneity of the masses low and excellent reproducible. The kinetics of drug release remain under extreme climatic storage conditions (at least 1 month Storage at 50 ° C or at 30 ° C and 75% relative humidity) surprisingly stable (deviation in release Max. 20% absolute, cf. Table II).

The advantage of the extrusion process over other techniques like granulating and tableting is the simple technology, avoidance of solvents, minimized number and Amount of auxiliary substances, the possibility of producing solid Solutions, avoiding opportunities to segregate the Components, in other words in a reliably uniform Composition of the individual prolonged-release forms throughout Production. There are also the advantages of a continuous Process flow with high throughput with low material losses.

Examples

The parts by weight of active ingredient and polymers given in the table and lipophilic component and other excipients either premixed or directly in via separate dosing scales the feeding of a twin screw extruder (Werner & Pfleiderer, ZSK 30) entered. The melt extrusion was carried out with a Product throughput of approx. 3 to 4 kg / h. The temperatures of each Temperature zones ("shots") of the extruder were 30/150/100/100/100 ° C, the temperature of the heated nozzle bar is shown separately in the table. The nozzle bar had 7 holes á 1 mm in diameter. The one over the heated extruder nozzle bar emerging melt strands were cooled by air Hot cut pelletized with a knife roller granulator.

The drug release was determined using the impeller method (Paddle method according to USP XXI) measured. This in vitro test method is used to determine the solution rate of active ingredients Moldings, e.g. Tablets.

For this purpose, 900 ml of a phosphate buffer with a pH of 6.8 were heated to 37 ° C. in a 1 liter round-bottomed vessel. A suitable amount of pellets (approx. 300 mg) with a grain size of 1.25 to 1.60 mm was weighed out. The active ingredient release of the pellets in percent was determined in this no-change test according to USP XXI at a paddle speed of 100 rpm after 1, 2, 3, 4, 5, 6, 7 and 8 hours by UV spectroscopy.

Claims (8)

1. Slow-release matrix pellets with a spherical or lenticular shape and uniform maximum diameters in the range from 0.5 to 4 mm, composed of

   a) 0.1-87 % by weight of at least one biologically active compound,

   b) 5-50 % by weight of at least one water-insoluble polymer,

   c) 5-45 % by weight of at least one lipophilic component as plasticizer for polymer b),

   d) 3-40 % by weight of a natural or semisynthetic gel former,

   e) 0-50 % by weight of one or more conventional formulation aids.
2. Slow-release matrix pellets as claimed in claim 1, having the following concentrations of the components:

   a) 1-75 % by weight,

   b) 10-40 % by weight,

   c) 10-35 % by weight,

   d) 5-25 % by weight,

   e) 0-40 % by weight.
3. Slow-release matrix pellets as claimed in claim 1 or 2, wherein the maximum diameter is 0.8-2 mm.
4. Slow-release matrix pellets as claimed in any of claims 1 to 3, wherein the active substance (a) is pharmaceutical in nature.
5. A continuous one-stage process for producing slow-release matrix pellets as claimed in any of claims 1 to 4 by extrusion of the molten mixture of the components at 50-200°C and continuous shaping.
6. A process as claimed in claim 5, wherein extrusion is carried out at 50-180°C.
7. A process as claimed in claim 5, wherein extrusion is carried out at 60-150°C.
8. A process as claimed in any of claims 5 to 7, wherein hot-cut shaping takes place.